Olfactory Perception Regularities of Structurally Related γ-Lactones: Insights from OR2W1 Selectivity

Olfactory receptor recognition of odorants is generally considered to involve dynamic receptor-ligand interactions rather than a rigid lock-and-key mechanism. To investigate how structurally related odorants are differentially recognized, a homologous series of γ-lactones differing only in alkyl side-chain length was systematically evaluated using the human olfactory receptor OR2W1. Cellular assays demonstrated that OR2W1 activation initially increased and subsequently decreased with increasing side-chain length, with γ-nonalactone producing the strongest concentration-dependent response (EC50 = 40.27 ± 2.33 μM). Molecular modeling suggested that γ-nonalactone adopted the most favorable binding mode and exhibited the lowest predicted binding free energy toward OR2W1. Site-directed mutagenesis of representative binding-site residues further supported the functional evidence of the predicted receptor-ligand interactions. Collectively, these results suggest that the structural adaptability of the OR2W1 binding pocket contributes to the differential recognition of structurally related γ-lactones within a limited physicochemical space. This study provides molecular-level evidence for the structure-activity relationship governing γ-lactone recognition by OR2W1 and offers mechanistic insights into odorant recognition by broadly tuned human olfactory receptors.